Project Summary/Abstract Lymphedema is an incurable condition characterized by tissue swelling after lymphatic damage. It affects over 140 million individuals worldwide and is associated with poor quality of life due to extremity disability, disfigurement, and risk for recurrent limb-threatening infection. In the US, lymphedema is usually due to lymph node resection in association with the treatment of malignancies such as breast or pelvic tumors. There are currently no known medical therapies that can prevent or reverse the clinical progression of lymphedema in humans. However, recent data suggests that surgical transfer of vascularized lymph nodes (VLN) to replace damaged lymph nodes or divert lymphatic flow from a distal extremity may limit and even reverse disease progression. Since lymphatic damage and backflow is the root cause of lymphedema, we hypothesize that exogenous stimulation of lymphangiogenesis at the time of the initiating lymphatic injury may be an effective strategy to prevent and/or treat lymphedema. We have previously demonstrated that 9-cis retinoic acid (9-cis RA) can promote lymphangiogenesis in vitro and can limit lymphedema in vivo. The specific aims of this proposal are: 1) To elucidate the mechanism by which 9-cis RA acts to minimize surgically induced lymphedema in vivo; 2) To determine the minimal effective dose (MED) of 9-cis RA necessary to prevent post- surgical lymphedema; and 3) To determine effect of 9-cis RA on vascularized lymph node flap transfers (VLN) using a novel transgenic fluorescent lymphatic reporter rat. We expect data from these studies to support rapid translation to human clinical trials, especially since 9-cis RA (Alitretinoin) is already FDA approved. Data from this proposal has the potential to re-purpose 9-cis RA as the first pharmacologic agent used to significantly impact the onset and progression of secondary lymphedema. Dr. Alex Wong, the principal investigator of this grant, is a surgeon-scientist who has a long-term goal of becoming an independent investigator in the field of lymphedema. He goal is to become an expert in RA therapy for lymphedema and lead clinical trials using RA and other modalities. Dr. Young-Kwon Hong, PhD is the primary mentor for this grant, is an international expert in lymphagiogenesis and lymphedema. He is an established investigator with NIH R-series funding and has a solid track record in mentoring PhD and MD scientists to independence. The proposed career development plan that integrates scientific investigation, formal course work, and frequent meetings to assess scientific progression will be essential for Dr. Wong's goals towards independence.